This invention relates to vitamin D compounds, and more particularly to the use of 2-methylene-19-nor-vitamin D compounds to prevent and/or treat inflammatory bowel disease.
The natural hormone, 1α,25-dihydroxyvitamin D3 and its analog 1α,25-dihydroxyvitamin D2 are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, various side chain homologated vitamins and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Inflammatory bowel diseases (IBD) are immune mediated diseases of unknown etiology affecting the gastrointestinal (GI) tract. There are at least two distinct forms of IBD, ulcerative colitis and Crohn's disease. IBD are chronic recurring illnesses most commonly involving inflammation of the terminal ileum and colon, although these diseases can also affect many sites throughout the alimentary tract. Clearly, genetic factors predispose individuals to development of IBD (Podolosky 1991). In addition, the environment contributes to IBD development, and there is reason to believe that vitamin D may be an environmental factor which affects IBD. Vitamin D from sunlight exposure is less in areas where IBD occurs most often, as IBD is most prevalent in northern climates such as North America and Northern Europe (Podolosky 1991, Sonnenberg et al. 1991). A major source of vitamin D results from its manufacture via a photolysis reaction in the skin, and vitamin D available from sunlight exposure is significantly less in northern climates, and especially low during the winter (Clemens et al. 1982, DeLuca 1993). Dietary intake of vitamin D is problematic since there are few foods which are naturally rich in vitamin D. Weight loss occurs in 65-75% of patients diagnosed with Crohn's disease and 18-62% of patients with ulcerative colitis (Fleming 1995, Geerling et al. 1998). Vitamin deficiencies in general and vitamin D deficiency in particular have been shown to occur in IBD patients (Andreassen et al. 1998, Kuroki et al. 1993). To date the possible association between vitamin D status and the incidence and severity of IBD in humans or animals has not been studied. The anecdotal information suggests that vitamin D status could be an environmental factor affecting the prevalence rate for IBD and that the correlation warrants investigation.
The identification of vitamin D receptors in peripheral blood mononuclear cells sparked the early interest in vitamin D as an immune system regulator (Bhalla et al. 1983, Provvedini et al. 1983). In particular the CD4+ Th cells have vitamin D receptors and are therefore targets for vitamin D (Veldman et al. 2000). Hormonally active vitamin D (1,25-dihydroxycholecalciferol) suppressed the development of at least two experimental autoimmune diseases (Cantorna et al. 1996, Cantorna et al. 1998). In vitro 1,25-dihydroxycholecalciferol inhibited T cell proliferation and decreased the production of interleukin (IL)-2, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α (Lemire-1992). In vivo 1,25-dihydroxycholecalciferol injections were shown to inhibit the delayed type hypersensitivity reaction associated with the type-1 helper T (Th1) cell response (Lemire et al. 1991, Lemire et al. 1992). Vitamin D is a potent regulator of the immune system in general and T cells specifically.
For IBD, the immune mediated attack is against the GI tract (Niessner and Volk 1995, Podolosky 1991). T cells, which preferentially produce the Th1 cytokines (IL-2, IFN-γ, and TNF-α), have been shown to transfer Crohn's-like symptoms to naive mice (Aranda et al. 1997, Bregenholt and Claesson 1998) and the production of Th1 cytokines is associated with IBD in humans as well (Niessner and Volk 1995). 1,25-dihydroxycholecalciferol treatment has been shown to suppress the development of other T cell mediated experimental autoimmune diseases (multiple sclerosis, and arthritis; Cantorna et al. 1996, Cantoma et al. 1998). The hypothesis that vitamin D (through the production of 1,25-dihydroxycholecalciferol) would suppress the development and progression of IBD thus seemed credible. Cantorna in PCT application WO 01/42205 and Hayes et al in U.S. Pat. No. 6,358,939 both have reported that 1,25(OH)2D3 can prevent IBD in IL-10 knock-out mice. However, hypercalcemia can be a significant problem when 1,25(OH)2D3 is used to treat IBD.
Standard treatments of patients with IBD include short-term high dose and long term low dose prednisone use (Podolosky 1991, Andreassen et al. 1998). Prednisone and other corticosteroid therapies result in a decreased bone mineral density and many times result in higher risks for vertebral fracture (Andreassen et al. 1997, Andreassen et al. 1998). Vitamin D supplementation of patients on corticosteroids has been shown to prevent steroid induced bone loss (Buckley et al. 1996). The hormonally active form of vitamin D (1,25-dihydroxycholecalciferol) is known to increase bone mineralization when given to experimental animals (Cantorna et al. 1998) and people (Ongphiphadhanakul et al. 2000). Thus a further benefit of vitamin D and or 1,25-dihydroxycholecalciferol supplementation may be the maintenance of bone mineral density.